PPARγ is one of the nuclear receptors that express mainly in adipocytes. Activation of PPARγ is considered to not only promote differentiation or maturation of adipocytes, but also be involved in the improvement of insulin resistance in diabetes, macrophage's transformation into foam cells in arteriosclerosis, and the like. For example, it is considered that, by the activation of PPARγ and promotion of differentiation of adipocyte, insulin resistance caused by TNF-α, free fatty acid and the like is eliminated and a blood glucose lowering effect and the like are exhibited on type 2 diabetes. Therefore, a compound having a superior PPARγ activation activity is known to be useful as an anti-hyperglycemia, anti-hyperlipidemia, insulin sensitizer, therapeutic agent for diabetes, therapeutic agent for diabetic complications, impaired glucose tolerance improving agent, anti-arteriosclerosis, anti-obesity, anti-inflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated diseases and an agent for the prophylaxis or treatment of syndrome X. However, PPARγ activators may express adverse events as side effects in clinical use, such as heart weight gain, cardiac enlargement, edema, hydrothorax and the like. These side effects are considered to be the events associated with accumulation of body fluid caused by activation of PPARγ.
PTP is an enzyme that catalyzes dephosphorylation of phosphotyrosine in protein, and PTP-1B, LAR (leukocyte antigen-related) PTP, LRP and the like are known. In addition, PTP is considered to be a phosphatase that dephosphorylates, for example, insulin receptor and the like. It is known that PTP is involved in the regulated inhibition of insulin receptors through dephosphorylation of insulin receptors. Therefore, a pharmaceutical agent that selectively inhibits PTP (preferably PTP-1B) enhances signaling after binding of insulin to its receptor, by the activity and has a known potential of becoming a drug for the prophylaxis or treatment of, for example, diabetes, hyperglycemia, impaired glucose tolerance, obesity, hyperlipidemia, diabetes complication, gestational diabetes, polycystic ovary syndrome, malignant tumor, autoimmune disease, allergic disease, immunodeficiency, inflammatory disease, neuropathy, neurodegenerative disease, infectious disease and the like (particularly a drug for the prophylaxis or treatment of diabetes) (see Biochemical Journal, 1992, vol. 284, p. 569 and Science, 1999, vol. 283, p. 1544).
At present, vanadium derivatives, phosphotyrosine derivatives and the like are known as PTP-1B inhibitors. Due to the problems in the specificity of inhibitory activity, permeability into cells, toxicity and the like, however, they have not been put to practical use as yet.
While WO02/096880 discloses compounds having PPARγ activation activity, it is not known at all that the compounds have PTP inhibitory activity.